Although gangliosides are ubiquitous components of cell membranes, the function of these glycosphingolipids is obscure. We are developing several systems to investigate their function. (1) HeLa cells undergo a striking morphological differentiation in response to butyrate. This shape change is associated with induction of a specific glycosyltransferase and an increase in ganglioside content but not with alterations in surface glycoproteins. (2) Ganglioside GM1 is the presumed surface membrane receptor for cholera Toxin. A line of chemically-transformed mouse fibroblasts can not synthesize GM1. These GM1-deficient cultured cells are unresponsive to cholera toxin; but following binding of (H3)-GM1 from the culture medium, the cells now respond to the toxin as measured by an increase in cyclic AMP. Other gangliosides cannot substitute for GM1 in these cells. (3) Certain gangliosides inhibit the binding of thyrotropin to thyroid membranes and the subsequent stimulation of adenylate cyclase. These same gangliosides are found in high amounts in thyroid membranes and induce a conformational change in the hormone. Cholera toxin partially competes with thyrotropin binding, undergoes a conformational change in the presence of GM1 and has a region of amino acid sequence homology with thyrotropin and related glycoprotein hormones. A similar mechanism of action of cholera toxin and glycoprotein hormones is indicated.